tbuckley/cabot-search huggingface dataset:
Filling the evidence void: exploration of coach and healthcare provider experiences working with pregnant and postpartum elite athletes – a qualitative study
Authors: Margie H Davenport, Lauren Ray, Autumn Nesdoly, Jane S Thornton, Rshmi Khurana, Tara-Leigh F McHugh
Journal: British Journal of Sports Medicine (2023)

Recent research grounded in the experiences of elite female athletes has shed light on the complex challenges of navigating sport environments that do not support or value pregnant or postpartum athletes. The purpose of this study was to explore the unique experiences of coaches and healthcare providers working with pregnant and postpartum elite athletes, and to identify actionable steps for research, policy and culture change to support them.Sixteen participants (five coaches, three physicians and eight physiotherapists), who have worked with pregnant and/or postpartum elite athletes within the last 5 years, participated in this qualitative study. Thirteen participants self-identified as women, and three as men. Data were generated via semistructured one-on-one interviews that were audiorecorded, transcribed verbatim and analysed through a process of content analysis.The findings of this research are represented by five main themes: (a) lack of female athlete reproductive research, (b) need for evidence-informed education and training, (c) need to develop evidence-based progression for sport participation in pregnancy and postpartum, (d) open communication to support athlete-centred care and (e) essential supports and changes required for pregnant/postpartum athletes.Findings from this study, which are grounded in the unique perspectives of coaches and healthcare providers, outline specific recommendations to inform policy and practices that support athletes through the perinatal period, such as developing evidence-based return-to-sport protocols.
Current and Future Treatment Landscape for Idiopathic Pulmonary Fibrosis
Authors: Francesco Bonella, Paolo Spagnolo, Chris Ryerson
Journal: Drugs (2023)

Idiopathic pulmonary fibrosis (IPF) remains a disease with poor survival. The pathogenesis is complex and encompasses multiple molecular pathways. The first-generation antifibrotics pirfenidone and nintedanib, approved more than 10 years ago, have been shown to reduce the rate of progression, increase the length of life for patients with IPF, and work for other fibrotic lung diseases. In the last two decades, most clinical trials on IPF have failed to meet the primary endpoint and an urgent unmet need remains to identify agents or treatment strategies that can stop disease progression. The pharmacotherapeutic landscape for IPF is moving forward with a number of new drugs currently in clinical development, mostly in phase I and II trials, while only a few phase III trials are running. Since our understanding of IPF pathogenesis is still limited, we should keep focusing our efforts to deeper understand the mechanisms underlying this complex disease and their reflection on clinical phenotypes. This review discusses the key pathogenetic concepts for the development of new antifibrotic agents, presents the newest data on approved therapies, and summarizes new compounds currently in clinical development. Finally, future directions in antifibrotics development are discussed.
Somatic estrogen receptor α mutations that induce dimerization promote receptor activity and breast cancer proliferation
Authors: Seema Irani, Wuwei Tan, Qing Li, Weiyi Toy, Catherine Jones, Mayur Gadiya, Antonio Marra, John A Katzenellenbogen, Kathryn E Carlson, Benita S Katzenellenbogen, Mostafa Karimi, Ramya Segu Rajappachetty, Isabella S Del Priore, Jorge S Reis-Filho, Yang Shen, Sarat Chandarlapaty
Journal: Journal of Clinical Investigation (2023)

Physiologic activation of estrogen receptor α (ERα) is mediated by estradiol (E2) binding in the ligand-binding pocket of the receptor, repositioning helix 12 (H12) to facilitate binding of coactivator proteins in the unoccupied coactivator binding groove. In breast cancer, activation of ERα is often observed through point mutations that lead to the same H12 repositioning in the absence of E2. Through expanded genetic sequencing of breast cancer patients, we identified a collection of mutations located far from H12 but nonetheless capable of promoting E2-independent transcription and breast cancer cell growth. Using machine learning and computational structure analyses, this set of mutants was inferred to act distinctly from the H12-repositioning mutants and instead was associated with conformational changes across the ERα dimer interface. Through both in vitro and in-cell assays of full-length ERα protein and isolated ligand-binding domain, we found that these mutants promoted ERα dimerization, stability, and nuclear localization. Point mutations that selectively disrupted dimerization abrogated E2-independent transcriptional activity of these dimer-promoting mutants. The results reveal a distinct mechanism for activation of ERα function through enforced receptor dimerization and suggest dimer disruption as a potential therapeutic strategy to treat ER-dependent cancers.
State Legislator Social Media Posts About the 988 Suicide and Crisis Lifeline
Authors: Jonathan Purtle, Michael Soltero, Margaret E. Crane, Anna-Michelle Marie McSorley, Molly Knapp, Christopher W. Drapeau
Journal: JAMA Network Open (2023)

This cross-sectional study examines the volume and content of state legislator social media posts about the 988 National Suicide and Crisis Lifeline.
Phase II Clinical Trial of Pembrolizumab and Chemotherapy Reveals Distinct Transcriptomic Profiles by Radiologic Response in Metastatic Triple-Negative Breast Cancer
Authors: Avia D. Wilkerson, Prerana Bangalore Parthasarathy, Nickolas Stabellini, Carley Mitchell, Paul G. Pavicic, Pingfu Fu, Amit Rupani, Hana Husic, Patricia A. Rayman, Shadi Swaidani, Jame Abraham, G. Thomas Budd, Halle Moore, Zahraa Al-Hilli, Jennifer S. Ko, Joseph Baar, Timothy A. Chan, Tyler Alban, C. Marcela Diaz-Montero, Alberto J. Montero
Journal: Clinical Cancer Research (2023)

Abstract Purpose: A single arm, phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple-negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, overall survival (OS), and identify pathologic and transcriptomic correlates of response to therapy. Patients and Methods: Patients with ≤2 prior therapies for metastatic disease were treated with CNP regardless of tumor programmed cell death-ligand 1 status. Core tissue biopsies were obtained prior to treatment initiation. ORR was assessed using a binomial distribution. Survival was analyzed via the Kaplan–Meier method. Bulk RNA sequencing was employed for correlative studies. Results: Thirty patients were enrolled. The ORR was 48.0%: 2 (7%) complete responses (CR), 11 (41%) partial responses (PR), and 8 (30%) stable disease (SD). The median DOR for patients with CR or PR was 6.4 months [95% confidence interval (CI), 4–8.5 months]. For patients with CR, DOR was &amp;gt;24 months. Overall median PFS and OS were 5.8 (95% CI, 4.7–8.5 months) and 13.4 months (8.9–17.3 months), respectively. We identified unique transcriptomic landscapes associated with each RECIST category of radiographic treatment response. In CR and durable PR, IGHG1 expression was enriched. IGHG1high tumors were associated with improved OS (P = 0.045) and were concurrently enriched with B cells and follicular helper T cells, indicating IGHG1 as a promising marker for lymphocytic infiltration and robust response to chemo-immunotherapy. Conclusions: Pretreatment tissue sampling in mTNBC treated with CNP reveals transcriptomic signatures that may predict radiographic responses to chemo-immunotherapy.
Time to Treat the Climate and Nature Crisis as One Indivisible Global Health Emergency
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Thomas Benfield, Kirsten Bibbins-Domingo, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Robert Mash, Peush Sahni, Wadeia Mohammad Sharief, Paul Yonga, Chris Zielinski
Journal: JAMA Oncology (2023)
FDG PET/CT in a Case of Thoracic SMARCA4-Deficient Undifferentiated Tumor
Authors: Jia Guo, Zhongjian Liao, Qing Chen, Aisheng Dong, Mouqing Huang
Journal: Clinical Nuclear Medicine (2023)

Abstract Thoracic SMARCA4-deficient undifferentiated tumor is a rare, newly recognized poorly differentiated tumor with poor prognosis. FDG PET/CT findings of thoracic SMARCA4-deficient undifferentiated tumor are rarely reported. We describe FDG PET/CT findings in a case of thoracic SMARCA4-deficient undifferentiated tumor. The tumor presented as a pleural mass, destroyed the adjacent ribs, and showed intense FDG uptake with SUV max of 12.7. This case indicates that thoracic SMARCA4-deficient undifferentiated tumor should be included in the differential diagnosis of FDG-avid pleural lesions.
Elevated FAPI Activity in Ulcerative Fungal Esophagitis
Authors: Yang Xie, Wenxin Tang, Huipan Liu, Yue Chen
Journal: Clinical Nuclear Medicine (2023)

Abstract We report a case of ulcerative fungal esophagitis with elevated activity of 18 F-FDG and 68 Ga-FAPI (fibroblast-activating protein inhibitor). Our findings suggest that ulcerative fungal esophagitis should be considered in the differential diagnosis of cancer-like esophageal mass with increased 68 Ga-FAPI uptake.
Time to treat the climate and nature crisis as one indivisible global health emergency
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Thomas Benfield, Kirsten Bibbins-Domingo, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Robert Mash, Peush Sahni, Wadeia Mohammad Sharief, Paul Yonga, Chris Zielinski
Journal: JNCI Journal of the National Cancer Institute (2023)
Perinatal Trajectories of Maternal Depressive Symptoms in Prospective, Community-Based Cohorts Across 3 Continents
Authors: Michelle Z. L. Kee, Andrea Cremaschi, Maria De Iorio, Helen Chen, Tina Montreuil, Tuong Vi Nguyen, Sylvana M. Côté, Kieran J. O’Donnell, Gerald F. Giesbrecht, Nicole Letourneau, Shiao Yng Chan, Michael J. Meaney
Journal: JAMA Network Open (2023)

Importance Depressive symptoms during pregnancy influence the development and health of the offspring, underscoring the need for timely intervention. However, the course of depressive symptoms across the perinatal period remains unclear, thus complicating screening and referral guidelines. Objective To examine the course and stability of depressive symptoms across the perinatal period in multiple, ethnically diverse independent observational cohorts. Design, Setting, and Participants This cohort study included self-reported depressive symptoms at multiple time points from 7 prospective cohorts spanning 3 continents (United Kingdom: Avon Longitudinal Study of Parents and Children from 1991 to 1995; Canada: Maternal Adversity, Vulnerability and Neurodevelopment from 2003 to 2007; Montreal Antenatal Well-being Study from 2019 to 2022; Alberta Pregnancy Outcomes and Nutrition from 2009 to 2014; and Singapore: Growing Up in Singapore Toward Healthy Outcomes from 2009 to 2013; Singapore Preconception Study of Long-Term Maternal and Child Outcomes from 2015 to 2019; and Mapping Antenatal Maternal Stress from 2019 to 2022). Participants were recruited either during preconception or pregnancy and observed into the postnatal period. All data from each cohort were analyzed from July 2022 to April 2023. Main Outcomes and Measures Self-reported depressive symptoms from pregnancy to 2 years following childbirth using either the Edinburgh Postnatal Depression Scale or the Center for Epidemiological Studies Depression were analyzed independently within each cohort using item response theory (IRT) techniques. K -means clustering was used to identify groups of participants with similar trajectories. Results A total of 11 563 pregnant women (mean [SD] age, 29 [5] years; 569 [4.9%] East Asian women; 304 [2.6%] Southeast Asian women; 10 133 [87.6%] White women) self-reported depressive symptoms from pregnancy to 2 years following childbirth. Analytic methods from Item Response Theory identified 3 groups of mothers based on depressive symptoms: low, mild, and high levels in each of the 7 cohorts. Mothers within and across all cohorts had stable trajectories of maternal depressive symptoms from pregnancy onwards. Mothers with clinical levels of depressive symptoms likewise showed stable trajectories from pregnancy into the postnatal period. Conclusions and Relevance In this study, trajectories of depressive symptoms remained stable from pregnancy across the perinatal period, a finding that conflicts with a continuing emphasis on postpartum or postnatal onset of depression that persists in some health policy guidelines. Interventions and public health initiatives should focus on reducing depressive symptoms during pregnancy in addition to following birth.
TNF-α protects from exacerbated myocarditis and cardiac death by suppressing expansion of activated heart-reactive CD4+ T cells
Authors: Filip Rolski, Karolina Tkacz, Kazimierz Węglarczyk, Grzegorz Kwiatkowski, Paweł Pelczar, Agnieszka Jaźwa-Kusior, Anna Bar, Gabriela M Kuster, Stefan Chłopicki, Maciej Siedlar, Gabriela Kania, Przemysław Błyszczuk
Journal: Cardiovascular Research (2023)

Abstract Aims Tumour necrosis factor α (TNF-α) represents a classical pro-inflammatory cytokine, and its increased levels positively correlate with the severity of many cardiovascular diseases. Surprisingly, some heart failure patients receiving high doses of anti-TNF-α antibodies showed serious health worsening. This work aimed to examine the role of TNF-α signalling on the development and progression of myocarditis and heart-specific autoimmunity. Methods and results Mice with genetic deletion of TNF-α (Tnf+/− and Tnf−/−) and littermate controls (Tnf+/+) were used to study myocarditis in the inducible and the transgenic T cell receptor (TCRM) models. Tnf+/− and Tnf−/− mice immunized with α-myosin heavy chain peptide (αMyHC) showed reduced myocarditis incidence, but the susceptible animals developed extensive inflammation in the heart. In the TCRM model, defective TNF-α production was associated with increased mortality at a young age due to cardiomyopathy and cardiac fibrosis. We could confirm that TNF-α as well as the secretome of antigen-activated heart-reactive effector CD4+ T (Teff) cells effectively activated the adhesive properties of cardiac microvascular endothelial cells (cMVECs). Our data suggested that TNF-α produced by endothelial in addition to Teff cells promoted leucocyte adhesion to activated cMVECs. Analysis of CD4+ T lymphocytes from both models of myocarditis showed a strongly increased fraction of Teff cells in hearts, spleens, and in the blood of Tnf+/− and Tnf−/− mice. Indeed, antigen-activated Tnf−/− Teff cells showed prolonged long-term survival and TNF-α cytokine-induced cell death of heart-reactive Teff. Conclusion TNF-α signalling promotes myocarditis development by activating cardiac endothelial cells. However, in the case of established disease, TNF-α protects from exacerbating cardiac inflammation by inducing activation-induced cell death of heart-reactive Teff. These data might explain the lack of success of standard anti-TNF-α therapy in heart failure patients and open perspectives for T cell–targeted approaches.
Immunosurveillance in clinical cancer management
Authors: Guido Kroemer, Timothy A. Chan, Alexander M. M. Eggermont, Lorenzo Galluzzi
Journal: CA A Cancer Journal for Clinicians (2023)

The progression of cancer involves a critical step in which malignant cells escape from control by the immune system. Antineoplastic agents are particularly efficient when they succeed in restoring such control (immunosurveillance) or at least establish an equilibrium state that slows down disease progression. This is true not only for immunotherapies, such as immune checkpoint inhibitors (ICIs), but also for conventional chemotherapy, targeted anticancer agents, and radiation therapy. Thus, therapeutics that stress and kill cancer cells while provoking a tumor-targeting immune response, referred to as immunogenic cell death, are particularly useful in combination with ICIs. Modern oncology regimens are increasingly using such combinations, which are referred to as chemoimmunotherapy, as well as combinations of multiple ICIs. However, the latter are generally associated with severe side effects compared with single-agent ICIs. Of note, the success of these combinatorial strategies against locally advanced or metastatic cancers is now spurring successful attempts to move them past the postoperative (adjuvant) setting to the preoperative (neoadjuvant) setting, even for patients with operable cancers. Here, the authors critically discuss the importance of immunosurveillance in modern clinical cancer management.
PD-1-expressing macrophages and CD8 T cells are independent predictors of clinical benefit from PD-1 inhibition in advanced mesothelioma
Authors: Krisztian Homicsko, Panagiota Zygoura, Maxim Norkin, Stephanie Tissot, Nicholas Shakarishvili, Sanjay Popat, Alessandra Curioni-Fontecedro, Mary O'Brien, Anthony Pope, Riyaz Shah, Patricia Fisher, James Spicer, Amy Roy, David Gilligan, Sylvie Rusakiewicz, Ekaterina Fortis, Nesa Marti, Roswitha Kammler, Stephen P Finn, Georges Coukos, Urania Dafni, Solange Peters, Rolf A Stahel
Journal: Journal for ImmunoTherapy of Cancer (2023)

Few tissue biomarkers exist to date that could enrich patient with cancer populations to benefit from immune checkpoint blockade by programmed cell death protein 1/ligand-1 (PD-/L-1) inhibitors. PD-L1 expression has value in this context in some tumor types but is an imperfect predictor of clinical benefit. In malignant pleural mesothelioma, PD-L1 expression is not predictive of the benefit from PD-1 blockade. We aimed to identify novel markers in malignant pleural mesothelioma to select patients better.We performed a multiplex-immune histochemistry analysis of tumor samples from the phase III PROMISE-meso study, which randomized 144 pretreated patients to receive either pembrolizumab or standard second-line chemotherapy. Our panel focused on CD8+T cell, CD68+macrophages, and the expression of PD-1 and PD-L1 on these and cancer cells. We analyzed single and double positive cells within cancer tissues (infiltrating immune cells) and in the stroma. In addition, we performed cell neighborhood analysis. The cell counts were compared with clinical outcomes, including responses, progression-free and overall survivals.We confirmed the absence of predictive value for PD-L1 in this cohort of patients. Furthermore, total CD8 T cells, CD68+macrophages, or inflammatory subtypes (desert, excluded, inflamed) did not predict outcomes. In contrast, PD-1-expressing CD8+T cells (exhausted T cells) and PD-1-expressing CD68+macrophages were both independent predictors of progression-free survival benefit from pembrolizumab. Patients with tumors simultaneously harboring PD1+T cells and PD-1+macrophages benefited the most from immune therapy.We analyzed a large cohort of patients within a phase III study and found that not only PD-1+CD8 T cells but also PD-1+CD68+ macrophages are predictive. This data provides evidence for the first time for the existence of PD-1+macrophages in mesothelioma and their clinical relevance for immune checkpoint blockade.
Two-year MRI-defined structural damage and patient-reported outcomes following surgery or exercise for meniscal tears in young adults
Authors: Stine Haugaard Clausen, Søren T Skou, Mikael Ploug Boesen, Dimitar Ivanon Radev, Engin Yeter Kurt, Camma Damsted, Per Hölmich, Martin Lind, Sofus Tørring, Christin Isaksen, Claus Varnum, Martin Englund, Jonas Bloch Thorlund
Journal: British Journal of Sports Medicine (2023)

Objective To investigate potential differences in structural knee joint damage assessed by MRI and patient-reported outcomes (PROMs) at 2-year follow-up between young adults randomised to early surgery or exercise and education with optional delayed surgery for a meniscal tear. Methods A secondary analysis of a multicentre randomised controlled trial including 121 patients (18–40 years) with an MRI-verified meniscal tear. For this study, only patients with 2-year follow-up were included. The main outcomes were the difference in worsening of structural knee damage, assessed by MRI using the Anterior Cruciate Ligament OsteoArthrits Score, and the difference in change in the mean score of four Knee Injury and Osteoarthritis Outcome Score (KOOS 4 ) subscales covering pain, symptoms, function in sport and recreation, and quality of life, from baseline to 2 years. Results In total, 82/121 (68%) patients completed the 2-year follow-up (39 from the surgical group and 43 from the exercise group). MRI-defined cartilage damage had developed or progressed in seven (9.1%) patients and osteophytes developed in two (2.6%) patients. The worsening of structural damage from baseline to 2-year follow-up was similar between groups. The mean (95% CI) adjusted differences in change in KOOS 4 between intervention groups from baseline to 2 years was −1.4 (−9.1, 6.2) points. The mean improvement in KOOS 4 was 16.4 (10.4, 22.4) in the surgical group and 21.5 (15.0, 28.0) in the exercise group. No between group differences in improvement were found in the KOOS subscales. Conclusions The 2-year worsening of MRI-defined structural damage was limited and similar in young adult patients with a meniscal tear treated with surgery or exercise with optional delayed surgery. Both groups had similar clinically relevant improvements in KOOS 4 , suggesting the choice of treatment strategy does not impact 2-year structural knee damage or PROMs. Trial registration number NCT02995551 .
The nociceptin/orphanin FQ receptor partial agonist sunobinop promotes non-REM sleep in rodents and patients with insomnia
Authors: Garth T. Whiteside, Donald J. Kyle, Ram P. Kapil, Alessandra Cipriano, Ellie He, Mingyan Zhou, Manjunath S. Shet, Michele Hummel, Terri Knappenberger, Kazuya Fukumura, Yoshiyuki Matsuo, Masahiro Uehira, Shuichi Hiroyama, Nozomi Takai, Sandra K. Willsie, Stephen C. Harris
Journal: Journal of Clinical Investigation (2023)

The potent and partial agonist sunobinop activates the nociceptin/orphanin-FQ peptide receptor and promotes non-REM sleep in rodents and patients with insomnia.